I. PATHOGNESIS OF CEREBRAL ISCHEMIA: The discovery of ET-1 and NO has greatly contributed to our understanding of the functional changes of many organs under physiological and pathological conditions (e.g., hypertension, atherosclerosis, and stroke). In the brain, the endothelium is the main producer of ET-1 and NO, although both of these substances are produced by a variety of cellular elements (e.g., smooth muscle, glia, and neurons). Endothelial ET-1 was shown to induce NO secretion that, in turn, reduced the production of ET-1. These reactions, which are mediated by ETA and ETB receptors, contribute to the maintenance of vascular tone and control of circulation (e.g., cerebral blood flow and blood pressure) as well as blood-brain barrier function. The regulatory mechanisms involved in this interplay have recently been shown to involve Ca2+ mobilization, cytoskeletal rearrangements and vasodilator-stimulated phosphoprotein changes that are mediated by c-GMP/c-GMP kinase system. The latest studies identify additional interactions between ET-1 and the vasorelaxant 2-AG, an endogenous cannabimimetic derivative of arachidonic acid. 2-AG inhibited ET-1-stimulated intracellular Ca2+ mobilization in a dose-dependent manner; this response is partially inhibited by treatment with the selective CB1-receptor antagonist SR141716A. The observed 2-AG reduction of ET-1 stimulated Ca2+ mobilization is mediated by G-protein, the IP metabolic pathway, and Ca2+-stimulated K+ channels. The inhibitors of nitric oxide synthase (L-NAME), cyclooxygenase (indomethacin) and lipoxygenase (nordihydroguaretic acid) have no effect. The interplay between 2-AG and ET-1 also involves cytoskeletal rearrangements of F-actin and vimentin. In addition, 2-AG induces phosphorylation of vasodilator-stimulated protein (VASP) by a c-AMP (and not c-GMP) mediated reaction. These findings implicate 2-AG/ET-1 interactions in cerebral capillary and microvascular endothelial responses and provide a potential alternative pathway for abrogating ET-1-inducible microvascular effects in the brain. II. TOLERANCE TO CEREBRAL ISCHEMIA: Endogenous tolerance to ischemia. Although young animals are known to be less susceptible than adults to brain ischemia, the mechanism(s) responsible for such resistance are not fully understood. Heat shock proteins (HSC73 and HSP72) are increased in variety of stresses (i.e., hyperthermia, ischemia) and their implied neuroprotective role has been investigated in ischemic brain of young and adults. The constitutive expression of the HSC73 mRNA and protein was significantly higher in the hippocampus of young than of adult sham-operated gerbils. The HSC73 mRNA expression following ischemia was greater in the CA1 layer of young than adult gerbils. HSC73 immunoreactivity was not significantly changed after ischemia/reperfusion in adult hippocampus, while it decreased in young gerbils. Ischemia/reperfusion led to induction of HSP72 mRNA expression throughout the hippocampus of both young and adult gerbils. HSP72 mRNA induction was more intense and sustained in the CA1 subfield of young gerbils; this was associated with both a marked induction of HSP72 proteins and neuronal survival. The transient expression of HSP72 mRNA in the CA1 layer of adult gerbils was not associated with a subsequent synthesis of HSP72 protein, but was linked to neuronal loss. It is suggested that the enhanced endogenous ischemic tolerance of CA1 neurons observed in young animals is related to the higher transcriptional and translational activities for HSP72 mRNA and proteins.